RNA Sequencing Facilitates Quantitative Analysis of Lupus (MRL/lpr) and ControlMRL/mpjMouse Microglia Tanscriptomes

Up to 75% of systematic lupus erythematosus (SLE) patients experience neuropsychiatric (NP) symptoms, called neuropsychiatric SLE (NPSLE), yet the underlying mechanisms remain elusive. Microglia control synaptic pruning during early postnatal brain development. The process in NPSLE remains unclear. Here, we show that microglia-coordinated elimination of synaptic terminals participated in NPSLE in MRL/lpr mice, a lupus-prone murine model. We elucidated that lupus mice developed increased depression- and anxiety-like behaviors and persistent phagocytic microglia reactivation before overt peripheral lupus pathology. Microglial engulfment of synapses explained behavioral disorders. To elucidate the mechanism of synaptic pruning by microglia, we sequenced the gene expression in sorted microglia from both lupus (MRL/lpr) mice and the wild-type (MRL/mpj) controls. RNA sequencing in microglia from control(MRL/mpj) and lupus (MRL/lpr) mice, in triplicate.系统性红斑狼疮（systemic lupus erythematosus, SLE）患者中，多达75%会出现神经精神（neuropsychiatric, NP）症状，这类病症被称为神经精神性狼疮（neuropsychiatric SLE, NPSLE），但其潜在发病机制仍尚不明确。小胶质细胞（microglia）在出生后早期脑发育过程中调控突触修剪，而NPSLE中的这一过程仍未得到阐明。本研究发现，在狼疮易感小鼠模型MRL/lpr中，小胶质细胞协同介导的突触终末清除参与了NPSLE的发生发展。我们发现，在出现显性外周狼疮病理特征之前，狼疮小鼠已表现出抑郁样、焦虑样行为增多，且持续存在吞噬性小胶质细胞活化。小胶质细胞对突触的吞噬作用可解释上述行为障碍。为阐明小胶质细胞介导突触修剪的分子机制，我们对狼疮（MRL/lpr）小鼠与野生型（wild-type, MRL/mpj）对照小鼠的分选小胶质细胞进行了基因表达测序。本实验对对照组（MRL/mpj）与狼疮组（MRL/lpr）小鼠的小胶质细胞进行了RNA测序（RNA sequencing），每组设置三次生物学重复。